EHA 2016
Causes and consequences of microRNA dysregulation in cancer
Prof Carlo Croce - Ohio State University, Columbus, USA
I’m going to talk about the role of microRNA in cancer, in particular in leukaemias and lymphomas because a few years ago we found that genetic alterations in microRNA cause a very common leukaemia called chronic lymphocytic leukaemia. That was the first evidence of a role of non-coding genes in cancer.
Could you tell us more about the background of this?
The background is that it was known that in CLL there was a deletion in one chromosome, chromosome 13, and we thought that in that region there should have been a tumour suppressor involved in CLL. So we looked for this tumour suppressor, we scanned the region very carefully and we couldn’t find the gene. Finally we got the idea there could be a gene coding for non-coding RNA and we found that was absolutely true and the great majority of CLL, patients with CLL, have a deletion of these microRNAs. So that was an astounding discovery because it went against the dogma that was that all the cancer genes were protein coding genes.
How is this changing your research today?
We are continuing in the same area and we take advantage of changes in microRNA, dysregulation microRNA for better diagnosis and prognosis of cancer to follow the success of therapy. In addition we hope that sooner or later, we hope soon, microRNA and anti-microRNA will become drugs for the treatment of some tumours.
Are there any subtypes of CLL that are most or least susceptible to mRNA regulation?
Essentially these two microRNAs, miR-15 and 16, are deleted in between 70-90% of CLL, so in most of them. So that makes those CLLs sensitive to a microRNA treatment. But the most fascinating thing is that ages ago, in fact in 1984, my lab cloned a gene that turned out to be very important and I named this gene BCL-2. Later on it was found that BCL-2 is overexpressed in CLL and now there is a new drug against BCL-2, ABT199, that has been shown to be very successful in the treatment of patients with CLL. But we found that a target of miR-15 and 16, these two microRNAs that are deleted in CLL, target BCL-2. So microRNAs are negative regulators of gene expression so in CLL the loss of these two microRNAs causes the overexpression of BCL-2 and you treat the patient with an anti-BCL-2 drug and that’s very successful, you can cause complete remission.
When it comes to treatment microRNAs are famously short-lived, very transient, is that a problem?
That is really not true. MicroRNAs naturally if they are free in blood have a limited lifespan but not shorter than many drugs. When they are encapsulated, for example in exosome or microvesicle, they can last a very, very, very long time. So one of the ways people are using microRNA now is in microsphere or another way that can protect the microRNA for some time in order to increase the half-life of microRNA. That can be done quite readily now.
Is there something that you’d like to offer as a summary, as a conclusion?
MicroRNAs are providing another dimension in cancer because in every cancer we have shown dysregulation of microRNA occurs. We can take advantage of this dysregulation for developing new therapies. In some cases the therapy will be like the treatment if it’s an anti-BCL-2 because microRNA dysregulation causes overexpression of BCL-2. In other cases microRNA will be used and I’m sure that within a few years you will have the development of microRNA based therapies.
